Murine myeloproliferative disorder as a consequence of impaired collaboration between dendritic cells and CD4 T cells

Stéphanie Humblet-Baron, John S. Barber, Carlos P. Roca, Aurelie Lenaerts, Pandelakis Koni, Adrian Liston

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Dendritic cells (DCs) are a key cell type in the initiation of the adaptive immune response. Recently, an additional role for DCs in suppressing myeloproliferation was discovered. Myeloproliferative disorder (MPD) was observed in murine studies with constitutive depletion of DCs, as well as in patients with congenital deficiency in DCs caused by mutations in GATA2 or IRF8. The mechanistic link between DC deficiency and MPD was not predicted through the known biology and has remained an enigma. Prevailing models suggest numerical DC deficiency leads to MPD through compensatory myeloid differentiation. Here, we formally tested whether MPD can also arise through a loss of DC function without numerical deficiency. Using mice whose DCs are deficient in antigen presentation, we find spontaneous MPD that is characterized by splenomegaly, neutrophilia, and extramedullary hematopoiesis, despite normal numbers of DCs. Disease development was dependent on loss of the MHC class II (MHCII) antigen-presenting complex on DCs and was eliminated in mice deficient in total lymphocytes. Mice lacking MHCII and CD4 T cells did not develop disease. Thus, MPDwas paradoxically contingent on the presence of CD4 T cells and on a failure of DCs to activate CD4 T cells, trapping the cells in a naive Flt3 ligand-expressing state. These results identify a novel requirement for intercellular collaboration between DCs and CD4 T cells to regulate myeloid differentiation. Our findings support a new conceptual framework of DC biology in preventing MPD in mice and humans.

Original languageEnglish (US)
Pages (from-to)319-330
Number of pages12
JournalBlood
Volume133
Issue number4
DOIs
StatePublished - Jan 24 2019

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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